A variety of diseases and disorders, including pre-malignancy, overt malignancy and immunodeficiency, are related to malfunction within the lympho-hematopoietic system. Some of these conditions could be alleviated and/or cured by repopulating the lympho-hematopoietic system with progenitor cells, which when triggered to differentiate would overcome the patient's deficiency. Therefore, the ability to initiate and regulate hematopoiesis is of great importance (McCune et al., 1988, Science 241:1632).
In humans, a form of successful therapy is bone marrow transplantation. Apart from the use of bone marrow transplantation in the treatment of leukemia, it is now frequently being used in other neoplasia (Epstein and Slease, 1985, Surg. Ann. 17:125). This type of therapy, however, is both painful (for donor and recipient) because of the involvement of invasive procedures and can cause severe and even fatal complications to the recipient, particularly with allogeneic transplant and related Graft Versus Host Disease (GVHD) results. Therefore, the risk of GVHD restricts the use of bone marrow transplantation to patients with otherwise fatal diseases. An alternative approach to therapy for hematopoietic disorders is the use of growth factors or cytokines to stimulate blood cell development in a recipient (Dexter, 1987, J. Cell Sci. 88:1; Moore, 1991, Annu. Rev. Immunol. 9:159).
The process of blood cell formation, by which a small number of self-renewing stem cells give rise to lineage specific progenitor cells that subsequently undergo proliferation and differentiation to produce the mature circulating blood cells has been shown to be at least in part regulated by specific hormones. These hormones are collectively known as hematopoietic growth factors, (Metcalf, 1985, Science 229:16; Dexter, 1987, J. Cell Sci. 88:1; Golde and Gasson, 1988, Scientific American, July:62; Tabbara and Robinson, 1991, Anti-Cancer Res. 11:81; Ogawa, 1989, Environ. Health Presp. 80:199; Dexter, 1989, Br. Med. Bull. 45:337). With the advent of recombinant DNA technology, a number of these molecules have now been cloned and expressed in recombinant form (Souza et al., 1986, Science 232:61; Gough et al., 1984, Nature 309:763; Yokota et al., 1984, Proc. Natl. Acad. Sci. U.S.A. 81:1070; Kawasaki et al., 1985, Science 230:291).
These growth factors have been studied in their structure, biology and even therapeutic potential. Some of the most well characterized factors include erythropoietin (EPO), stem cell factor (SCF), granulocyte macrophage colony stimulating factor (GM-CSF), macrophage colony stimulating factor (M-CSF), granulocyte colony stimulating factor (G-CSF), and the interleukins. These factors act on different cell types at different stages during blood cell development, and their potential uses in medicine include lessening the need for blood transfusions, speeding bone marrow recovery following transplantation and cytotoxic cancer therapy, correcting immunosuppressive disorders, wound healing, and activation of the immune response. (Golde and Gasson, 1988, Scientific American, July:62). Apart from inducing proliferation and differentiation of hematopoietic progenitor cells, such cytokines have also been shown to activate a number of functions of mature blood cells (Stanley et al., 1976, J. Exp. Med. 143:631; Schrader et al., 1981, Proc. Natl. Acad. Sci. U.S.A. 78:323; Moore et al., 1980, J. Immunol. 125:1302; Kurland et al., 1979, Proc. Natl. Acad. Sci. U.S.A. 76:2326; Handman and Burgess, 1979, J. Immunol. 122:1134; Vadas et al., 1983, Blood 61:1232; Vadas et al., 1983, J. Immunol. 130:795), including influencing the migration of mature hematopoietic cells (Weibart et al., 1986, J. Immunol. 137:3584).
Although these growth factors have been shown to possess proliferative and/or differentiative effects on various hematopoietic cell lineages, they have not proven effective in many clinical disease settings. For example, myelodysplastic syndromes (MDS) comprise a diverse group of hematopoietic stem cell disorders characterized by ineffective blood cell production, progressive cytopenias and a variable risk of progression to acute leukemia (List et al., 1990, J. Clin. Oncol. 8:1424). Clinical trials of MDS patients treated with recombinant human granulocyte-macrophage colony-stimulating factor and recombinant human granulocyte-colony stimulating factor have shown that while these cytokines can restore granulocytopoiesis in treated patients, the efficacy is restricted to the granulocyte/monocyte lineage with little or no improvement in hemoglobin and/or platelet counts (Schuster et al., 1990, Blood 76 (Suppl.1):318a). When such patients were recently treated with recombinant human erythropoietin, a sustained improvement in hemoglobin and/or decrease in transfusion requirement was achieved in only less than 25% of patients (Besa et al., 1990, 76 (Suppl.1):133a; Hellstrom et al., 1990, 76 (Suppl.1):279a; Bowen et al., 1991, Br. J. Haematol. 77:419). Thus, there remains a need for an effective agent for the treatment of marrow failure states such as MDS.
Furthermore, cytokines are both difficult and costly to produce. Because these factors are proteins, their production is not amenable to direct chemical synthesis. Moreover, their low endogenous expression levels and the limited growth rate of human cells make the natural production of these proteins extremely costly. Their production by recombinant methods also entails large economic costs and technical obstacles. Hence, none of these previously reported molecules provides both a biologically active and readily synthesized stimulator of hematopoietic progenitor cells for in vivo administration.